Assessments of fluid volume of the lung, as well as determination of cardiac output, are of importance for clinical medicine and physiological research. Acute respiratory insufficiency is a major cause of mortality in patients, being commonly a complication of various disturbances in lung fluid balance leading to the development of pulmonary edema. The latter can be caused by a number of factors and its appropriate treatment requires adequate diagnosis and early therapy.
Both direct and indirect methods for assessing the fluid volume of the lungs have been developed and thoroughly investigated for their potential significance and accuracy in clinical and experimental research. Generally only indirect, or non-distructive measures can be applied in clinical investigations, although they are not so accurate as direct ones. Among the indirect measurements are: lung mechanics and pulmonary gas exchange, non-gaseous and gaseous indicator-dilution procedures, measurement of transthoracic impedance and radiological methods. All of these, based on different physical principles of measurement, have specific limitations, for theoretical and methodologic reasons.
Lung mechanics are changed in edema due to progressive engorgement by edema fluid, which decreases lung compliance and increases resistance to airflow. But, these changes are not specific for edema, being caused also by changes in alveolar surface tension or vascular hypertension. Also, non-specific changes in lung mechanics due to bronchoconstriction can alter the results significantly.
Gas exchange disturbances usually occur in lung edema. However, these disturbances are also non-specific and provide information more of a qualitative, than of a quantitative nature. Being influenced by numerous variables of ventilation and perfusion, anatomical and physiological shunting and various feedback regulatory mechanisms gas exchange disturbances are of importance mainly for the detecting final alveolar flooding stage of pulmonary edema.
Radiological methods are mostly of a semi-quantitative character, based on special radiographic criteria and are not likely to provide objective or fast monitoring information, although it is the most widely available pulmonary edema diagnostic procedure. Utilizing others kinds of external energy sources, for example, microwave sources and corresponding detectors (U.S. Pat. No 4,488,559, Iskander M.) also does not provide enough accuracy and quantitiveness for lung water measurements.
As lung tissue is a conductor of electric current and lung conductivity varies strikingly with inflation and water content of lung tissue, changes in transthoracic impedance can be used for the lung water measurements. Limitations of this method are in the inability to distinguish conductivity of the lung itself from the surrounding tissue (chest wall), low sensitivity, demands of stable chest geometry and electrode positioning and inability to determine absolute values.
Indicator dilution procedures are most commonly used for quantitative measurements of lung water content. Indicators are injected intravascularly and indicator concentrations are measured in the systemic arterial blood or by external probes in the case of gamma-emitting isotopes. Two indicators: one non-permeable (vascular reference) and the other permeable (extravascular reference) are utilized. The vascular reference indicator remains confined to the vascular volume, while the permeable indicator readily diffuses into the extravascular compartment of the lung.
For the extravascular reference tritiated water or heat seem to be most appropriate, having the highest diffusion coefficients. Reference, for example , U.S. Pat. No. 4,230,126, Elings V. From the time-course of both indicators appearance and concentration in systemic arterial blood, it is possible to calculate the blood flow through the lung (vascular reference) and extravascular water content using the mean transit time difference between both indicators. These methods are well grounded by mathematical analysis of the processes of non-steady-state transfer of indicators in the fluid stream and its exchange with surrounding tissues. There are different mathematical and technical approaches to performing the measurements and calculating the results. Such details as injection site and form, methods of indicator collection and detection, as well as the site of collection may substantially influence the results. Adequate measurements require appropriate mixing of indicator at the entrance and exit of the lung, correction for the delay imposed by the collection catheter and the position of the collection catheter. In the ideal situation the collection catheter would be located in the left atrium, but that involves additional technical problems in positioning the catheter.
The principal theoretical limitation of the method is the perfusion-dependant distribution of the extravascular indicator. If some portions of the lungs are poorly perfused, as is often true in lung diseases, it is difficult to obtain correct mean transit times due to incomplete recovery of tracer (flow limited). Recirculation of indicator is another serious problem because the slowly perfused portions of the lung may empty during the period of recirculation. Improper extrapolation of the indicator-dilution curve downslope is the reason why standard indicator dilution curves measure only a fraction of 40-90% of the lung thermal mass. Since lung tissue is composed of different types of organic materials, the solubility of indicators in water and lipids is important. For example, different permeable indicators yield different extravascular volumes (diffusion limited).
Further, the main problem preventing its wide clinical use is the invasiveness of the procedure. Most techniques require positioning of catheters for indicator injection and collection in the pulmonary artery and aorta respectively. Catheterization of the heart, especially puncturing of a large artery are complicated procedures, often accompanied by various complications - clotting, embolism etc., and can not be recommended as routine procedures. Positioning of the probes outside the chest without direct contact with the arterial bloodstream significantly decreases the accuracy of the measurements.
The above-mentioned drawbacks can be eliminated by using high-energy indicators and external scanning over the chest. Scanning procedures may permit more accurate evaluation of poorly perfused regions and retention of the indicator, as well as measurements of regional water content. Such determinations of lung water with the gamma-indicator .sup.22 -Na were used by Weidner in 1956, and by Kety's (1949) measurements of tissue perfusion. This procedure never became clinically popular because of considerable exposure to radioactivity and uncertainty regarding tracer distribution in cells. Others indicators, such as .sup.99 Tc-DTPA are being currently used. As this indicator is extracellular, it is not possible to distinguish between the plasma and interstitial water volumes. Uncertainty regarding the contribution of thoracic wall activity exists. The method also requires employing of expensive and sophisticated apparatus.
A different approach is used in methods utilizing soluble gas absorption by the lung tissue. Such measurements of lung tissue volume have been studied, since Cander and Forster used the inert gas acetylene for this purpose in 1959. The method is based on measuring the concentration of exhaled soluble gas after inhalation of a gas mixture with known concentration of the test gas. The soluble gas disappears from the airways and alveolar spaces due to its solution in lung tissues and blood. Constant blood flow via the lungs provides continuous extraction of the test gas from the lungs, so that pulmonary blood flow is also determined in these measurements. The solubility of the gas is of critical importance for the determination of lung water.
One of the main limitations of the soluble gas technique involves the back extrapolation of the disappearance curve to zero time of the soluble gas following multiple breathholds of the test-gas mixture. These back-extrapolation calculations are sensitive to a variety of measurement errors. Some factors which might occasion systematic errors are: cardiac output changes during the breathhold maneuvers, inhomogenities in the lung ventilation/perfusion ratios an inhomogenities of the lung deflation pattern. Also the method is sensitive to alterations in ventilation distribution which can be critical in pulmonary edema due to airway closure.
Application of the technique demands expensive and accurate apparatus for precisely measuring the gas concentration such as a mass spectrometer. Also the method is not useful in very sick patients, because the procedure requires rather complicated breathing procedures with the special gas mixture.
Although this method is capable of providing accurate enough measurement of lung water and cardiac output, the complexity and expense of the related gas concentration processing apparatus has significantly limited its widespread commercial application.
Various methods have been proposed for the measurement of cardiac output or pulmonary blood flow alone, without measuring lung water content. Most of them are also invasive, employing intravascular catheters or probes. The pioneering method was by Fick (1870), which was based on the measurement of oxygen consumption and the arterial-venous O.sub.2 concentration difference. But the method requires obtaining arterial and mixed venous blood samples. Single indicator dilution methods are also used for blood flow determination. These are referred, for example, to U.S. Pat. Nos. 4,024,873, Antoshkiw et al., 4,329,993, Lieber et al.
Other invasive methods use different principles of fluid flow measurement--measurement of the differential temperature that results from localized heating of the blood (U.S. Pat. Nos. 3,359,974, Khalil, 3,798,967,Gieles et al.), electromagnetic energy (U.S. Pat. No. 3,347,224, Adams) or ultrasonic devices (U.S. Pat. No. 4,802,490, Johnston), or local heating or cooling of the tissue itself (U.S. Pat. No. 4,802,489, Nitzan ). All these methods tend to be invasive, which is their main disadvantage.
It is therefore, the principal object of the new invention to provide a non-invasive method for pulmonary blood flow rate determination and pulmonary tissue volume determination, using heat as the permeable indicator of lung tissue volume and permitting non-invasiveness of the measurement. The method depends upon the lung'ability to humidify and heat the inspired air to the lung's own temperature over a wide range of breathing conditions, and upon easily performed measurements on expired air.